This invention is related to branched chain amino acid-dependent amino transferase (BCAT) inhibitors. The invention is also directed to the use of BCAT inhibitors as neuro-protective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, chronic pain, neuropathic pain, glaucoma, CMV retinitis, diabetic retinopathy, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer""s disease, Parkinsonism, amyotrophic lateral sclerosis (ALS), and Huntington""s Disease.
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer""s disease, Parkinson""s disease, and Huntington""s disease.
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson""s disease (Klockgether T., Turski L., Ann. Neurol., 1993;34:585-593), human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer""s disease (Francis P. T., Sims N. R., Procter A. W., Bowen D. M., J. Neurochem., 1993;60(5):1589-1604, and Huntington""s disease (see Lipton S., TINS, 1993;16(12):527-532; Lipton S. A., Rosenberg P. A., New Eng. J. Med., 1994;330(9):613-622; and Bigge C. F., Biochem Pharmacol, 1993;45:1547-1561, and referenced cited therein). NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
U.S. Pat. No. 5,352,683 discloses the treatment of chronic pain with a compound which is an antagonist of the NMDA receptor.
U.S. Pat. No. 4,902,695 discloses certain competitive NMDA antagonists that are useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative diseases such as Alzheimer""s disease and Huntington""s disease.
U.S. Pat. No. 5,192,751 discloses a method of treating urinary incontinence in a mammal which comprises administering an effective amount of a competitive NMDA antagonist.
The invention relates BCAT inhibitor compounds of Formula I 
wherein:
R3 is H, halogen, alkyl, carboxy, alkoxy, substituted alkoxy; R1, R2, R4 and R5 are independently, H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, NO2, halogen, or CF3;
R6 or R7 are independently, H, halogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, C(CH2)nxe2x80x94NHSO2-aryl, C(CH2)nxe2x80x94NHSO2-substituted aryl, (CH2)nxe2x80x94NHSO2-alkyl, (CH2)nxe2x80x94NHSO2-substituted alkyl, (CH2)nxe2x80x94NHSO2-arylalkyl, (CH2)nxe2x80x94NHSO2-substituted arylalkyl, NHSO2-aryl, NHSO2-substituted aryl, NHSO2-alkyl, NHSO2-substituted alkyl, NHSO2-arylalkyl, NHSO2-substituted arylalkyl, (CH2)n-aryl, (CH2)n-substituted aryl, (CH2)n-alkyl, (CH2)n-substituted alkyl, O-aryl, O-substituted aryl, O-alkyl, O-substituted alkyl, O-arylalkyl, O-substituted arylalkyl, (CH2)nxe2x80x94SO2NH-aryl, (CH2)nxe2x80x94SO2NH-substituted aryl, (CH2)nxe2x80x94SO2NH-alkyl, (CH2)nxe2x80x94SO2NH-substituted alkyl, (CH2)nxe2x80x94C(O)NH-arylalkyl, (CH2)nxe2x80x94C(O)NH-substituted arylalkyl, (CH2)nxe2x80x94C(O)NH-aryl, (CH2)nxe2x80x94C(O)NH-substituted aryl, (CH2)nxe2x80x94C(O)NH-alkyl, (CH2)nxe2x80x94C(O)NH-substituted alkyl, (CH2)nxe2x80x94SO2NH-arylalkyl, (CH2)nxe2x80x94SO2NH-substituted arylalkyl, (CH2)nxe2x80x94NH2, (CH2)nxe2x80x94NH-aryl, (CH2)nxe2x80x94NH-substituted aryl, (CH2)nxe2x80x94NH-alkyl, (CH2)nxe2x80x94NH-substituted alkyl, (CH2)nxe2x80x94NH-arylalkyl, (CH2)nxe2x80x94NH-substituted arylalkyl, (CH2)nxe2x80x94NHSO2-aryl, (CH2)nxe2x80x94NHSO2-substituted aryl, (CH2)nxe2x80x94NHSO2-alkyl, (CH2)nxe2x80x94NHSO2-substituted alkyl, (CH2)nxe2x80x94NHC(O)-arylalkyl, (CH2)nxe2x80x94NHC(O)-substituted arylalkyl, (CH2)nxe2x80x94NO2, (Cxe2x89xa1C)-alkyl. (Cxe2x89xa1C)-substituted alkyl, (Cxe2x89xa1C)-arylalkyl, (Cxe2x89xa1C)-substituted arylalkyl, (Cxe2x89xa1C)-aryl, or (Cxe2x89xa1C)-substituted aryl; and
n is 0, 1, 2, or 3.
or a pharmaceutically acceptable salt, ester, prodrug, or amide thereof;
where there is more than one stereoisomer, each chiral center may be independently R or S; or a pharmaceutically acceptable salt, ester, prodrug, or amide thereof;
The invention also relates to compounds of Formula I, wherein R1, R2, R3, R4, and R5 are hydrogen; and R6 or R7 is xe2x80x94NHSO2-aryl, xe2x80x94NHSO2-substituted aryl, xe2x80x94NHSO2-alkyl, or xe2x80x94NHSO2-substituted alkyl.
The invention also relates to compounds selected from:
Benzoic acid, 4-nitro-2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-amino-2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(2,4,6-trichlorophenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[[4-(trifluoromethyl)phenyl]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(3,4-dimethoxyphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[[(4-phenoxy)benzene]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(2-chloro-6methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[(methylsulfonyl)amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-ethylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-n-propylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-n-butylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-n-pentylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-fluorophenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[phenylsulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
4-Benzylamino-benzoic acid 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(3-methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
4-Phenoxybenzoic acid, 2-[(3-methyl)phenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[3-bromophenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[2-chlorophenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[2-(trifluoromethoxy)phenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[(4-methyl-3-nitro)phenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[2-trifluorophenylsulfonyl]hydrazide;
4-(1,1-Dimethylethyl)-benzoic acid 2-(phenylsulfonyl)hydrazide;
[1,1xe2x80x2-Biphenyl]-4-carboxylic acid 2-(phenylsulfonyl)hydrazide;
3-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;
2-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;
4-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;
4-Benzyloxybenzoic acid, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-methoxyphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
4-Iodo-benzoic acid, 2-(phenylsulfonyl)hydrazide;
4-Phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide;
Phenethyl-benzoic acid, 2-(phenylsulfonyl)hydrazide;
4-(3-Cyclohexyl-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;
4-(3-Cyclohexyl-3-hydroxy-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;
4-(3-Cyclohexyl-3-hydroxy-1-propyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;
4-(3,3-Dimethyl-1-butynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide; and
4-(3,3-Dimethyl-1-butyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide.
The invention also relates to a method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer""s disease, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease and Down""s syndrome, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, treating anxiety, psychosis, convulsions, chronic pain, neuropathic pain, diabetic retinopathy, glaucoma, CMV retinitis, urinary incontinence, and inducing anesthesia, as well as enhancing cognition, and preventing opiate tolerance and withdrawal symptoms, comprising administering to an animal in need of such treatment an effective amount of any one of the BCAT inhibitors of the present invention, or a pharmaceutically acceptable salt thereof.
The present invention also includes a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of Formula I and a pharmaceutically acceptable carrier.